Using a rate-frequency curve method to assess the rewarding properties of morphine in the intracranial self-stimulation paradigm in rats.

Intracranial self-stimulation (ICSS) is a sophisticated paradigm that can be used to assess the rewarding properties of drugs of abuse such as cocaine and amphetamine. Initial studies using this method to assess brain stimulation reward (BSR) examined the enhancement of response rates after drug administration. In the mid to late 1980s several groups began implementing paradigms to assess the direct rewarding effects of drugs of abuse that, for the most part, are independent of rate (i.e., progressive-ratio, auto-titration, rate-frequency curve), providing a representative assessment of a drugs rewarding effects. However, some drugs such as morphine and ethanol, which are known to have abuse potential, have sedative effects that may impede the ability to accurately quantify rewarding effects, even in these rate-independent paradigms. Few studies to date report effects of morphine in the ICSS paradigm and those that do appear to be inconsistent, lack robustness, have not been reproducible by other groups, or require inconvenient experimental designs. Here, we demonstrate a reliable and robust method to assess the rewarding effects of morphine using the rate-frequency curve paradigm.

Route of administration affects the ability of naltrexone to reduce amphetamine-potentiated brain stimulation reward in rats.

Opioid receptor antagonism has been shown to attenuate behavioral and neurochemical effects of amphetamine in humans and rodents. The effects of acute (oral or subcutaneous) or extended-release naltrexone (XR-NTX) were tested on the reward-enhancing effects of amphetamine using the intracranial self-stimulation (ICSS) paradigm. Acute exposure to drugs of abuse reduces the locus of rise (LOR) in the ICSS procedure, reflecting enhanced brain stimulation reward (BSR). Rats were treated once a day with naltrexone orally (PO; 5.0 mg/kg) or subcutaneously (SC; 0.5 mg/kg) for four consecutive days and tested with D-amphetamine (0.5 mg/kg, intraperitoneal) in the ICSS paradigm 30 minutes later on days 1 and 4. Separate groups of rats received XR-NTX (50 mg/kg, SC) or placebo microspheres (similar mass to XR-NTX, SC) on day 0 and tested with D-amphetamine in the ICSS paradigm on days 4, 14, 21, 28 and 41 after administration. Naltrexone plasma concentrations were determined for each amphetamine testing session using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). In rats pretreated with naltrexone acutely, amphetamine-potentiated BSR did not differ from vehicle-pretreated rats on either day 1 or day 4 (25-30% decrease in LOR). In XR-NTX-pretreated rats, amphetamine-potentiated BSR was reduced by 64 and 70% on days 4 and 14, respectively, compared to placebo microsphere-treated controls. This effect dissipated by day 21. Naltrexone plasma concentrations were comparable across all treatment groups (14-30 ng/ml) on days 1, 4 and 14. In summary, an extended-release formulation of naltrexone results in significant attenuation of psychostimulant-enhanced BSR that is not observed with acute naltrexone.